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Background: Circular RNAs (circRNAs) are stable, covalently closed non-coding RNAs formed by reverse splicing of precursor mRNA. They play critical roles in various biological processes, including insulin secretion and metabolism. However, their function in avian skeletal muscle's response to insulin remains poorly understood. This study aimed to comprehensively identify insulin-responsive circRNAs and explore their temporal and breed-specific regulation in poultry. Results: Using strand-specific RNA sequencing (ssRNA-Seq) on the pectoralis muscles of both Arbor Acres (AA) broilers and Silky fowls following insulin administration (5 IU/kg.BW, PBS as control). We identified 2,027 muscle circRNAs. Insulin-responsive circRNAs were detected in Silky fowls (29) and broilers (45) at 120 min, and in broilers (20) at 15 min post-injection. These circRNAs are enriched in processes such as exocrine pancreas development, response to exogenous stimuli, and regulation of intracellular signal transduction, likely mediated through a circRNA-miRNA network. Fewer insulin-responsive circRNAs were shared between time points in broilers (1) or between breeds (3) at 120 min. We further characterized a conserved insulin-responsive circRNA (circINSR), formed by exon 2 of the Insulin Receptor (INSR). The circINSR showed a similar spatiotemporal expression pattern to INSR, but exhibited distinct changes post-insulin administration. In broilers, INSR expression was dynamically modulated, while circINSR was downregulated only at 15 min (P < 0.01). Conversely, glucose did not change muscle circINSR but increased INSR at 10 min (P < 0.01). Energy restriction significantly downregulated circINSR (P < 0.01) without affecting INSR levels, and pyruvate had no effect on either circINSR or INSR levels. Conclusion: This study reveals the dynamic and breed-specific roles of circRNAs, particularly circINSR, in avian skeletal muscle's response to insulin. The distinct regulation of circINSR and INSR under various metabolic conditions suggests a complex regulatory mechanism. These findings provide novel insights into the molecular basis of insulin signaling in avian species and highlight the potential of circRNAs as biomarkers for metabolic regulation. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM), both type 1 and type 2, has been linked to decreased performance across a number of cognitive function categories, with more recent studies emphasizing the contribution of DM mediated dementia. Despite the therapeutic advantages of antidiabetic medications for the management of DM mediated cognitive dysfunction (CD), the majority of these pharmaceuticals are linked to a number of negative side effects, raising questions about their long-term advantages. Botanical medicines, which often have low toxicity and adverse effects, are supported by some latter research. These medicines are attracting increased interest from researchers studying traditional herbal remedies owing to the minimal side effects for prevention and managing DM and CD in developing and developed countries. To emphasize the health benefits of okra (Abelmoschus esculentus) against DM and CD. Different databases, including PubMed, Google Scholar, and Scopus, were searched with a combination of keywords. The available research on the health benefits of okra against DM and CD is compiled in this study which indicates that okra has the ability to manage DM and CD. It will serve as a base for further investigation into the okra preparation for its potential commercial production as a therapeutic agent for DM and CD. Highlights: • Diabetes mellitus (DM) is emerging as a serious global health issue. • Cognitive dysfunction (CD), a neurodegenerative disease, negatively affects memory. • DM and CD are correlated with each other and have a complex mechanism. • Disturbed insulin secretion sensitivity in insulin receptors activates oxidative stress. • Okra polysaccharides reverse DM and CD by regulating insulin signaling. [ABSTRACT FROM AUTHOR]

Insulin is a pleiotropic hormone that elicits its metabolic and mitogenic actions through numerous rapid and reversible protein phosphorylations. The temporal regulation of insulin's intracellular signaling cascade is highly complex and insufficiently understood. We conduct a time-resolved analysis of the global insulin-regulated phosphoproteome of differentiated human primary myotubes derived from satellite cells of healthy donors using high-resolution mass spectrometry. Identification and tracking of ~13,000 phosphopeptides over time reveal a highly complex and coordinated network of transient phosphorylation and dephosphorylation events that can be allocated to time-phased regulation of distinct and non-overlapping subcellular pathways. Advanced network analysis combining protein-protein-interaction (PPI) resources and investigation of donor variability in relative phosphosite occupancy over time identifies novel putative candidates in non-canonical insulin signaling and key regulatory nodes that are likely essential for signal propagation. Lastly, we find that insulin-regulated phosphorylation of the pre-catalytic spliceosome complex is associated with acute alternative splicing events in the transcriptome of human skeletal muscle. Our findings highlight the temporal relevance of protein phosphorylations and suggest that synchronized contributions of multiple signaling pathways form part of the circuitry for propagating information to insulin effector sites. The temporal regulation of intracellular insulin signaling is not well studied. Here the authors conducted a time-resolved analysis of the global insulin-regulated phosphoproteome in human muscle cells, revealing synchronized signaling pathways for propagating information to insulin effector sites. [ABSTRACT FROM AUTHOR]

Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin’s actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B–mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide–synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes. [ABSTRACT FROM AUTHOR]

Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time. Using this framework, we found that the PIK3CAH1047R oncogene was not a simple, constitutive activator of the pathway as often presented. Dose-dependent expression of PIK3CAH1047R in human cervical cancer and induced pluripotent stem cells corrupted the fidelity of growth factor-induced information transfer, with preferential amplification of epidermal growth factor receptor (EGFR) signaling responses compared to insulin-like growth factor 1 (IGF1) and insulin receptor signaling. PIK3CAH1047R did not only shift these responses to a higher mean but also enhanced signaling heterogeneity. We conclude that oncogenic PIK3CAH1047R corrupts information transfer in a growth factor-dependent manner and suggest new opportunities for tuning of receptor-specific PI3K pathway outputs for therapeutic benefit. Synopsis: A single-cell signaling framework is developed for quantitative measurements of information flow within the phosphoinositide 3-kinase (PI3K) pathway, enabling high-resolution studies of growth factor identity encoding in PI3K signaling dynamics. Using this framework, the study shows how one of the most common oncoproteins, PI3KαH1047R, degrades the fidelity of growth factor-specific signal transfer in a dose-dependent manner. Cells with higher levels of PI3KαH1047R exhibit increased signaling and phenotypic heterogeneity, with evidence for selective amplification of epidermal growth factor receptor (EGFR) responses. This provides a view of PI3KαH1047R as a context-dependent modulator of signal processing, with new opportunities for exploiting PI3K signaling dynamics as a pharmacological target. A single-cell signaling framework is developed for quantitative measurements of information flow within the phosphoinositide 3-kinase (PI3K) pathway, enabling high-resolution studies of growth factor identity encoding in PI3K signaling dynamics. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is associated with excess cardiovascular risk, even after accounting for traditional cardiovascular risk factors, including glycaemia. Hence, there is an urgent need to document the metabolic abnormalities that contribute to the cardiovascular mortality gap in type 1 diabetes, and to examine whether cardioprotective type 2 diabetes medications prevent premature morbidity and mortality in this population. [ABSTRACT FROM AUTHOR]

Sperm cytoplasmic droplets (CDs) are remnants of cytoplasm that can cause a number of problems if it not shed from the sperm after ejaculation. Exosomes can rapidly bind to sperm, but it is not clear whether exosomes can affect the migration and shedding of CDs. We first extracted and characterized seminal plasma exosomes from boar semen containing sperm with low or high rates of CDs. Then, the transcriptomic and proteomic detection of these exosomes were performed to analyze the differences between the two groups of seminal plasma exosomes. The results revealed that 486 differentially expressed genes (DEGs), 40 differentially expressed proteins (DEPs), and 503 differentially expressed lncRNAs (DElncRNAs) were identified between the low CD rate group and high CD rate group. Integrative multi-omics analysis showed that exosome components may affect migration and shedding of cytoplasmic droplets by influencing cytoskeletal regulation and insulin signaling, including regulation of the actin cytoskeleton, ECM–receptor interaction, axon guidance, insulin secretion, and the insulin signaling pathway. Overall, our study systematically revealed the DEGs, DEPs, and DElncRNAs in seminal plasma exosomes between low CD rate semen and high CD rate semen, which will help broaden our understanding of the complex molecular mechanisms involved in the shedding of CDs. [ABSTRACT FROM AUTHOR]

MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes has gradually been elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) for ubiquitin-dependent degradation. Additionally, MG53 has been identified as a myokine/cardiokine that is secreted from striated muscles into the bloodstream, and circulating MG53 has further been shown to trigger insulin resistance by binding to the extracellular domain of the IR, thereby allosterically inhibiting insulin signaling. Conversely, findings have been reported from other studies that contradict these results. Specifically, no significant change in MG53 expression in striated muscles or serum has been observed in diabetic models, and the MG53-mediated degradation of IRS-1 may be insufficient to induce insulin resistance due to the compensatory roles of other IRS subtypes. Furthermore, sustained elevation of MG53 levels in serum or systemic administration of recombinant human MG53 (rhMG53) has shown no impact on metabolic function. In this article, we will fully characterize these two disparate views, strive to provide critical insights into their contrasts, and propose several specific experimental approaches that may yield additional evidence. Our goal is to encourage the scientific community to elucidate the effects of MG53 on metabolic diseases and the molecular mechanisms involved, thereby providing the theoretical basis for the treatment of metabolic diseases and the applications of rhMG53. [ABSTRACT FROM AUTHOR]

Background: Due to sexual dimorphism in growth of penaeid shrimp, all-female cultivation is desirable for the aquaculture industry. 17β-estradiol (E2) has the potential to induce the male-to-female sex reversal of decapod species. However, the mechanisms behind it remain poorly understood. This study aimed to investigate the effects of E2 immersion on the neuroendocrine system (the eyestalk ganglia, brain, thoracic ganglia, and ventral nerve cord) of the Pacific white shrimp Penaeus vannamei through comparative transcriptomic analyses of the control males (CM), E2-treated males without sex reversal (EM), and neo-females (NF). Results: Immersion in E2 at 2 mg/l from post-larvae (PL) 5 to 85 results in a skewed female-to-male ratio of 2.56: 1. The survival rate remains unaffected by E2 exposure, while a notable inhibition in growth is exclusively observed in the EM compared to the CM group. The transcriptome analysis result indicates that the observed retardation in growth of the EM may be attributed to the potential neuronal damage caused by the excessive neurotransmission, which in turn disrupts the PI3K-Akt signaling and cell cycle pathways. In contrast, the negatively regulated pathways of neuroactive ligand-receptor interaction and the dopaminergic synapse in the NF group suggest a potential impact of E2 on neuroplasticity through the modulation of neuroregulator binding and signaling, which affects the establishment of morphological differences and gender identity. Moreover, the activation of steroidogenesis and the inhibition of the insulin signaling may be associated with the success of E2-induced sex reversal. With these findings, a proposed mechanism of neuroendocrine system in decapods in response to E2 exposure is presented. Conclusions: The present study represents a first step in understanding the effects of E2 on the neuroendocrine system at the molecular level. The observed retardation in growth in the EM group may be attributed to the potential for neuronal damage and disruptions in the cell cycle and PI3K-Akt signaling pathways. Furthermore, the success of E2-induced sex reversal may be associated with the downregulation of neuroactive ligand-receptor interaction, dopaminergic synapse, and insulin signaling pathways, as well as the activation of steroidogenesis. These findings provide new insights into the mode of action of E2, and underscore the potential for large-scale production of all-female stocks in P. vannamei. [ABSTRACT FROM AUTHOR]

Insulin resistance is major factor in the development of metabolic syndrome and type 2 diabetes (T2D). We extracted 430 genes from literature associated with both insulin resistance and inflammation. The highly significant pathways were Toll-like receptor signaling, PI3K-Akt signaling, cytokine-cytokine receptor interaction, pathways in cancer, TNF signaling, and NF-kappa B signaling. Among the 297 common genes in all datasets of various T2D patients' tissues including blood, muscle, liver, pancreas, and adipose tissues, 71% and 60% of these genes were differentially expressed in pancreas (GSE25724) and liver (GSE15653), respectively. A total of 169 genes contain highly conserved motifs for various transcription factors involved in immune response, thereby suggesting coordinated expression. Through co-expression analysis, we obtained three modules. The respective modules had 78, 158, and 55 genes, and TRAF2, HMGA1, and RGS5 as hub genes. Further, we used the BioNSi pathways simulation tool and identified the following five KEGG pathways perturbed in four or more tissues, namely Toll-like receptor signaling pathway, RIG-1-like receptor signaling pathway, pathways in cancer, NF-kappa B signaling pathway, and insulin resistance pathway. The genes NFKBIA and IKBKB are common to all these five pathways. In addition, using the NF-κB computational activation model, we identified that the reversal of NF-κB constitutive activation through overexpression of NFKB1 (P50 homodimer), PPARG, PIAS3 could reduce insulin resistance by almost half of its original value. To conclude, co-expression studies, gene expression network simulation, and NF-κB computational modeling substantiate the causal role of NF-κB pathway in insulin resistance. These results taken together with other published evidence suggests that the TNF-TRAF2-IKBKB-NF-κB axis could be explored as a potential target in combination with available metabolic targets in the management of insulin resistance. [ABSTRACT FROM AUTHOR]

The glucagon‐like peptide‐1 receptor (GLP‐1R) plays an important role in regulating insulin secretion and reducing body weight, making it a prominent target in the treatment of type 2 diabetes and obesity. Extensive research on GLP‐1R signaling has provided insights into the connection between receptor function and physiological outcomes, such as the correlation between Gs signaling and insulin secretion, yet the exact mechanisms regulating signaling remain unclear. Here, we explore the internalization pathway of GLP‐1R, which is crucial for controlling insulin release and maintaining pancreatic beta‐cell function. Utilizing a reliable and sensitive time‐resolved fluorescence resonance energy transfer (TR‐FRET) internalization assay, combined with HEK293‐derived knockout cell lines, we were able to directly compare the involvement of different endocytic machinery in GLP‐1R internalization. Our findings indicate that the receptor internalizes independently of arrestin and is dependent on Gs and Gi/o activation and G protein–coupled receptor kinase phosphorylation. Mechanistically, we observed that the receptor undergoes distinct clathrin‐ and caveolae‐mediated internalization in HEK293 cells. This study also investigated the role of arrestins in GLP‐1R function and regulation. These insights into key endocytic components that are involved in the GLP‐1R internalization pathway could enhance the rational design of GLP‐1R therapeutics for type 2 diabetes and other GLP‐1R‐related diseases. [ABSTRACT FROM AUTHOR]

Preserving a large number of essential yet highly unstable ribosomal DNA (rDNA) repeats is critical for the germline to perpetuate the genome through generations. Spontaneous rDNA loss must be countered by rDNA copy number (CN) expansion. Germline rDNA CN expansion is best understood in Drosophila melanogaster, which relies on unequal sister chromatid exchange (USCE) initiated by DNA breaks at rDNA. The rDNA-specific retrotransposon R2 responsible for USCE-inducing DNA breaks is typically expressed only when rDNA CN is low to minimize the danger of DNA breaks; however, the underlying mechanism of R2 regulation remains unclear. Here we identify the insulin receptor (InR) as a major repressor of R2 expression, limiting unnecessary R2 activity. Through single-cell RNA sequencing, we find that male germline stem cells (GSCs), the major cell type that undergoes rDNA CN expansion, have reduced InR expression when rDNA CN is low. Reduced InR activity in turn leads to R2 expression and CN expansion. We further find that dietary manipulation alters R2 expression and rDNA CN expansion activity. This work reveals that the insulin pathway integrates rDNA CN surveying with environmental sensing, revealing a potential mechanism by which diet exerts heritable changes to genomic content. The germline maintains unstable essential ribosomal DNA (rDNA) repeats to ensure each generation inherits a functional genome, yet it's unclear how this activity is controlled. Here, the authors find the insulin receptor governs germline rDNA maintenance in response to genetic and dietary cues. [ABSTRACT FROM AUTHOR]

Integration of autonomic and metabolic regulation, including hepatic function, is a critical role played by the brain's hypothalamic region. Specifically, the paraventricular nucleus of the hypothalamus (PVN) regulates autonomic functions related to metabolism, such as hepatic glucose production. Although insulin can act directly on hepatic tissue to inhibit hepatic glucose production, recent evidence implicates that central actions of insulin within PVN also regulate glucose metabolism. However, specific central circuits responsible for insulin signaling with relation to hepatic regulation are poorly understood. As a heterogeneous nucleus essential to controlling parasympathetic motor output with notable expression of insulin receptors, PVN is an appealing target for insulin-dependent modulation of parasympathetic activity. Here, we tested the hypothesis that insulin activates hepatic-related PVN (PVNhepatic) neurons through a parasympathetic pathway. Using transsynaptic retrograde tracing, labeling within PVN was first identified 24 h after its expression in the dorsal motor nucleus of the vagus (DMV) and 72 h after hepatic injection. Critically, nearly all labeling in medial PVN was abolished after a left vagotomy, indicating that PVNhepatic neurons in this region are part of a central circuit innervating parasympathetic motor neurons. Insulin also significantly increased the firing frequency of PVNhepatic neurons in this subregion. Mechanistically, rapamycin pretreatment inhibited insulin-dependent activation of PVNhepatic neurons. Therefore, central insulin signaling can activate a subset of PVNhepatic neurons that are part of a unique parasympathetic network in control of hepatic function. Taken together, PVNhepatic neurons related to parasympathetic output regulation could serve as a key central network in insulin's ability to control hepatic functions. NEW & NOTEWORTHY: Increased peripheral insulin concentrations are known to decrease hepatic glucose production through both direct actions on hepatocytes and central autonomic networks. Despite this understanding, how (and in which brain regions) insulin exerts its action is still obscure. Here, we demonstrate that insulin activates parasympathetic hepatic-related PVN neurons (PVNhepatic) and that this effect relies on mammalian target of rapamycin (mTOR) signaling, suggesting that insulin modulates hepatic function through autonomic pathways involving insulin receptor intracellular signaling cascades. [ABSTRACT FROM AUTHOR]

Cell adhesion-dependent phosphorylation of insulin-like growth factor 1 receptor (IGF-1R) on its C-terminal tail (CT) at Tyr1250/1251 promotes receptor internalization and Golgi accumulation. We previously proposed that this phosphorylation is associated with cell migration and cancer aggressiveness, distinguishing IGF-1R activity from that of insulin receptor, which lacks these tyrosines. Here, we further investigated how adhesion signaling influences IGF-1R location and activity in migratory cancer cells and R-fibroblasts. We observed that IGF-1R, in triple-negative breast cancer tissues, is predominantly intracellular and dispersed from the plasma membrane compared with nontumor tissue. Datasets from basal-like breast cancer patients indicated a strong, positive correlation between IGF-1R protein expression and that of β1-integrin (ITGB1). In triple-negative breast cancer cells with high ITGB1 expression, suppressing ITGB1 enhanced IGF-1R stability and its retention at the plasma membrane, and reduced IGF-1R internalization during cell adhesion. In R- fibroblasts, we observed reduced IGF-1R autophosphorylation and Golgi accumulation when ITGB1 was suppressed. The stability of a Tyr1250/1251Phe (FF) IGF-1R mutant was less affected by ITGB1 suppression, indicating that Tyr1250/1251 phosphorylation is required for ITGB1- enhanced receptor internalization. Furthermore, a Tyr1250/1251Glu (EE) IGF-1R mutant exhibited a gain of cell migration and colony formation potential compared to WT IGF-1R or FF mutant. Tyr1250/1251 resides within the CT 1248SFYYS1252 motif, which engages the IGF-1R kinase domain. In silico, we investigated how mutation of these tyrosines may alter 1248SFYYS1252 conformation, dictating trajectory of the distal CT. We conclude that Tyr1250/1251 phosphorylation confers IGF-1R with unique protumorigenic signaling in a manner that is enhanced by ITGB1. [ABSTRACT FROM AUTHOR]

Smoking is widely regarded as a risk factor for type 2 diabetes because nicotine contributes to insulin resistance by desensitizing the insulin receptors in muscle, liver, or fat. Little is known, however, about the immediate regulation of islet hormonal output by nicotine, an agonist of ionotropic cholinergic receptors. We investigated this by imaging cytosolic Ca2+ dynamics in mouse and human islets using confocal microscopy and measuring glucagon secretion in response to the alkaloid from isolated mouse islets. Nicotine acutely stimulated cytosolic Ca2+ in glucagon-secreting α-cells but not in insulin-secreting β-cells. The 2.8- ± 0.5-fold (P < 0.05) increase in Ca2+, observed in >70% of α-cells, correlated well with a 2.5- ± 0.3-fold stimulation of glucagon secretion. Nicotine-induced elevation of cytosolic Ca2+ relied on influx from the extracellular compartment rather than release of the cation from intracellular depots. Metabotropic cholinergic signaling, monitored at the level of intracellular diacylglycerol, was limited to 69% of α-cells versus 94% of β-cells. We conclude that parasympathetic regulation of pancreatic islet hormone release uses different signaling pathways in β-cells (metabotropic) and α-cells (metabotropic and ionotropic), resulting in the fine-tuning of acetylcholine-induced glucagon exocytosis. Sustained nicotinic stimulation is, therefore, likely to attenuate insulin sensitivity by increasing glucagon release. Article Highlights: Smoking/nicotine is conventionally assumed to exacerbate the diabetic phenotype. The mechanisms are unclear. We sought to determine whether nicotine can directly and specifically affect pancreatic islet cell signaling, in particular, that of the α-cell. Using real-time microscopic imaging, electrophysiology, and ELISA, we found that nicotine selectively stimulated Ca2+ dynamics and hormone release in islet α-cells but not in β-cells. We propose that nicotinic sensitivity can underlie the distinct effects of parasympathetic signaling on islet α- and β-cells. [ABSTRACT FROM AUTHOR]

Aim: To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin‐mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin‐mediated glucose uptake. Methods: Seventeen adults with obesity (BMI: 36 ± 3 kg/m2) completed a 2 h hyperinsulinemic–euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]). Results: Insulin‐mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor‐β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin‐mediated Tyr phosphorylation of IRβ and downstream insulin‐signalling proteins in LOW. Conclusion: Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin‐mediated glucose uptake commonly found in adults with obesity. [ABSTRACT FROM AUTHOR]

Background: ROS1, a member of the sevenless subfamily of tyrosine kinase insulin receptors, promotes tumor cell survival, proliferation, and metastasis by activating the JAK/STAT, PI3K/AKT, and MAPK/ERK pathways. It only accounts for about 2% of total NSCLC cases. No cases of acquired ROS-1 rearrangement have been reported worldwide. Case presentation: We reported a case of lung adenocarcinoma without driver alteration that developed resistance to pembrolizumab and newly emerged CD74-ROS1 fusion, and achieved a partial response after entrectinib treatment. Conclusions: We hypothesize that the newly emerged ROS1 rearrangement occurs as the subset of cells harboring ROS1 gradually becomes the predominant pathological type of adenocarcinoma following pembrolizumab treatment. We propose that new therapeutic targets may emerge for this patient population following long-term immunotherapy. Thus, we advocate for regular monitoring of tumor genetic status, which could yield unexpected benefits. [ABSTRACT FROM AUTHOR]

The appetite of honeybees for food is crucial to their survival and reproduction, as they sustain their entire colony by collecting pollen and nectar for nutrients. Dopamine, an important neurotransmitter, regulates appetite and satiety. However, how dopamine regulates honeybee foraging behavior remains unexplored. In this study, we investigated dopamine expression in 23-day-old Apis mellifera under different food-wanting conditions and identified differentially expressed genes (DEGs) in the brains of honeybees using RNA sequencing technology. We showed that dopamine levels in honeybees starved for 2 h were higher than those sated after 2 h of starvation. RNA-seq results revealed there were differences in the expression of cytochrome P450-dependent monooxygenase (CYP9Q1) in honeybees, which regulated the sucrose sensitivity of honeybees under different intake states. Furthermore, CYP9Q1 targeted the expression of the insulin receptor substrate (IRS) to promote dopamine synthesis. Our findings emphasize the relationship between dopamine and honeybees' desire for food at the molecular level, providing a reference for further exploring the mechanism of food wanting. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in these processes within vWAT. While second-generation antipsychotics (SGAs) have significantly improved treatments for mental health disorders, their chronic use is associated with an increased risk of MetS. In this study, we explored the impact of SGAs on ADSCs to better understand their role in MetS and identify potential therapeutic targets. Our findings reveal that olanzapine disrupts lipid droplet formation during adipogenic differentiation, impairing insulin receptor endocytosis, turnover, and signaling. SGAs also alter the endolysosomal compartment, leading to acidic vesicle accumulation and increased lysosomal biogenesis through TFEB activation. PKCζ is crucial for the SGA-induced nuclear translocation of TFEB and acidic vesicle formation. Notably, inhibiting PKCζ restored insulin receptor tyrosine phosphorylation, normalized receptor turnover, and improved downstream signaling following olanzapine treatment. This activation of PKCζ by olanzapine is driven by increased phosphatidic acid synthesis via phospholipase D (PLD), following G protein-coupled receptor (GPCR) signaling activation. Overall, olanzapine and clozapine disrupt endolysosomal homeostasis and insulin signaling in a PKCζ-dependent manner. These findings highlight SGAs as valuable tools for uncovering cellular dysfunction in vWAT during MetS and may guide the development of new therapeutic strategies to mitigate the metabolic side effects of these drugs. [ABSTRACT FROM AUTHOR]

Juvenile hormone (JH) plays a pivotal role in regulating post‐emergence development and metabolism in previtellogenic female Aedes aegypti mosquitoes. In contrast, yolk protein precursor production and egg maturation after a blood meal are regulated by the steroid hormone 20‐hydroxyecdysone, the insulin‐like growth factor (IGF)/insulin signaling (IIS) pathway, and the mammalian target of rapamycin (mTOR) pathway. The role of IIS/mTOR signaling in female adults prior to blood feeding has not been thoroughly investigated. In this study, we identified a significant increase in the phosphorylation of key effector proteins in the IIS/mTOR signaling pathway, including eukaryotic translation initiation factor 4E‐binding protein 1 (4E‐BP1), ribosomal protein S6 kinase (S6K) and forkhead box protein O1 (FoxO1), in previtellogenic females. In vitro fat body culture experiments suggest that JH induces these phosphorylations through rapid nongenomic signaling mediated by the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt)/mTOR network. RNA interference experiments demonstrated that activation of IIS/mTOR signaling in previtellogenic females modulate metabolic gene expression, promoting the accumulation of energy reserves (glycogen and triglycerides), which influence mosquito fecundity. Additionally, depletion of either the insulin receptor (InR) or the JH receptor Methoprene‐tolerant (Met) in adult mosquitoes abolished the phosphorylation of these proteins, indicating that both receptors are involved in JH‐induced membrane‐initiated signal transduction. Although the precise mechanisms remain unclear, this study uncovers a novel function of the IIS/mTOR pathway in adult mosquitoes before blood feeding, as well as a new mode of JH action through its crosstalk with the IIS pathway. [ABSTRACT FROM AUTHOR]

Diabetes is characterized by prolonged hyperglycemia and disruptions in carbohydrate, lipid, and protein metabolism, stemming from inadequate insulin production, impaired insulin receptor functioning, or a combination of both. Conventional diabetes medications like biguanides and sulphonylureas, are widely used and raise concerns about potential side effects with prolonged usage. In this context, legumes emerge as promising candidates due to their significance in traditional diets globally and associated health benefits. Despite being challenging to digest due to anti-nutritive factors, germination, a simple bioprocessing technique, significantly enhances nutritional aspect of the seeds. This study focuses on Lablab purpureus, an underutilized legume, employing a metabolomic approach to explore compounds in germinated and non-germinated seeds. Metabolomic profiling identified 125 compounds in non-germinated and 80 compounds in germinated seeds, revealing unique compounds in each type with potential health benefits. The study identified therapeutically important metabolites such as alkaloids, flavonoids, terpenoids, and saponin in both the germinated and non-germinated seeds. A notable change in the phytochemical composition (total phenol, flavonoid, and total ascorbic acid content) of germinated seeds was observed compared to the non-germinated seeds flour. An increased fold change (1.15, 1.5 and 1.65) was observed in the total phenol, flavonoid, and total ascorbic acid content in germinated seeds compared to non-germinated seeds, alongside higher antioxidant levels in terms of DPPH, ABTS, and FRAP. The IC50 value for α-amylase inhibitory activity was noted to be 2.05 ± 0.05 mg/ml in germinated samples while 0.79 ± 0.00 mg/ml was observed in the non-germinated Lablab purpureus seeds. Therefore, displaying greater α-amylase inhibitory activity in the non-germinated seeds, possibly due to their unique biochemical composition. Nevertheless, even germinated seeds demonstrated appreciable α-amylase inhibitory activity. Therefore, these findings suggest that germination process significantly influences seed biochemistry and helps to raise the phytochemical composition, while the unique composition of the metabolites in the non-germinated seeds could have impact on the α-amylase inhibitory activity. Thus, study suggests Lablab purpureus as a promising functional food source with diverse health-promoting attributes, particularly in diabetes management. [ABSTRACT FROM AUTHOR]

Reproductive success requires considerable energy investment. Research has shown that some adipokines, i.e. the hormones produced in adipose tissue, affect reproductive functions by influencing all structures of the hypothalamic-pituitary-ovarian axis. Apelin is a recently identified member of the adipokine family. To the best of the authors' knowledge, this is the first study to investigate the gene and protein expression of the apelin system (the apelin hormone and the apelin receptor, APJ) in the anterior (AP) and posterior (PP) pituitary lobes of the domestic pig during different phases of the oestrous cycle (days 2 to 3, 10 to 12, 14 to 16, and 17 to 19) and in early pregnancy (days 10 to 11, 12 to 13, 15 to 16, and 27 to 28). It was also assumed that apelin participates in the regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and influences Akt, MAPK/Erk1/2, and AMPK signalling pathways in the AP during the oestrous cycle. Apelin, APJ mRNAs and proteins were detected in both pituitary lobes. Apelin was identified in gonadotropes, somatotropes, lactotropes, and thyrotropes. The study also revealed that apelin and APJ mRNA/protein levels fluctuate during the oestrous cycle and early gestation. Apelin affects basal, GnRH- and/or insulin-stimulated gonadotropin secretion in some phases of the cycle, as well as the phosphorylation of Akt, MAPK/Erk1/2, and AMPK proteins in AP cells. These findings suggest that apelin may be produced locally in the pituitary and that this gland is receptive to apelin's action. The study also suggest that apelin may influence female reproductive functions by controlling the release of LH and FSH from AP cells, and that it affects Akt, MAPK/Erk1/2, and AMPK signalling pathways. • Apelin and its receptor are expressed in porcine anterior and posterior pituitary. • Apelin and APJ expression levels change during the cycle and early pregnancy. • Apelin changes LH and FSH secretion by gonadotropes during the oestrous cycle. • Apelin affects Akt, MAPK/Erk1/2 and AMPK phosphorylation in the pituitary. • Apelin may play a role in the regulation of pituitary functions. [ABSTRACT FROM AUTHOR]

Signaling molecules such as fatty acids regulate a wide range of cellular activities and bodily functions. Free fatty acid receptors (FFARs) have recently been discovered in orphaned G-protein-coupled receptors (GPCRs). FFARs play a major role in insulin secretion and insulin resistance. These receptors have emerged as an attractive target for the management of type 2 diabetes mellitus (T2DM). FFAR4/GPCR120 are expressed in β-cells of the pancreas and can be regulated by medium- and long-chain fatty acids. Long-chain fatty acids have various biological functions beyond FFAR4 activation. FFAR4 plays an important role in regulating macrophage activation and can improve metabolic ailments associated with insulin resistance. FFAR4 activation may also be a promising therapeutic approach to addressing various metabolic and related disorders. The role of FFAR4 in T2DM has been briefly discussed in this review. Recent developments in FFAR4/GPCR120 agonists have also been reported, along with the mechanism by which GPCR120 agonists activate FFAR4. [ABSTRACT FROM AUTHOR]

Central insulin resistance has been linked to the development of neurodegenerative diseases and mood disorders. Various proteins belonging to the enzyme family of protein tyrosine phosphatases (PTPs) act as inhibitors of insulin signaling. Protein tyrosine phosphatase receptor type J (PTPRJ) has been identified as a negative regulator in insulin signaling in the periphery. However, the impact of PTPRJ on insulin signaling and its functional role in neuronal cells is largely unknown. Therefore, we generated a Ptprj knockout (KO) cell model in the murine neuroblast cell line Neuro2a by CRISPR‐Cas9 gene editing. Ptprj KO cells displayed enhanced insulin signaling, as shown by increased phosphorylation of the insulin receptor (INSR), IRS‐1, AKT, and ERK1/2. Further, proximity ligation assays (PLA) revealed both direct interaction of PTPRJ with the INSR and recruitment of this phosphatase to the receptor upon insulin stimulation. By RNA sequencing gene expression analysis, we identified multiple gene clusters responsible for glucose uptake and metabolism, and genes involved in the synthesis of various lipids being mainly upregulated under PTPRJ deficiency. Furthermore, multiple Ca2+ transporters were differentially expressed along with decreased protein biosynthesis. This was accompanied by an increase in endoplasmic reticulum (ER) stress markers. On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development. Taken together, PTPRJ emerges as a negative regulator of central insulin signaling, impacting neuronal metabolism and neurite outgrowth. [ABSTRACT FROM AUTHOR]

Simple Summary: Few studies have been conducted on the signaling mechanism underlying chilling-induced embryonic diapause termination in insects. In the current study, we compared temporal changes in expression levels of insulin (bombyxin-A6, -Y1, and -Z1), ecdysone signaling (ecdysteroid-phosphate phosphatase (EPPase) and E75A), sorbitol dehydrogenase 2 (SDH2), and metabolic-related (trehalose transporter 1 (Tret1) and trehalase 1 (Treh1)) genes between chilled Bombyx mori eggs and eggs kept at 25 °C. Our results showed that expressions of all the above-mentioned genes remained at very low levels in eggs kept at 25 °C. However, in chilled eggs, differential temporal changes were detected according to different genes, with bombyxin-A6 and EPPase gene expressions being maintained at relatively constant, high levels. Expressions of the SDH2 and bombyxin-Z1 genes decreased during the first 15 days, and then SDH2 gene expression began to increase on day 30 after chilling, followed by increased expression of the bombyxin-Z1 gene. Relatively higher GSK-3β phosphorylation and ecdysteroid levels were also found in chilled eggs. From these results, we suggest that the upregulation of insulin/ecdysone signaling in chilled eggs is related to chilling-induced egg diapause termination in B. mori. In the present study, we investigated the possible correlation between insulin/ecdysone signaling and chilling-induced egg diapause termination in Bombyx mori. Changes in insulin (bombyxin-Z1) and ecdysteroid-phosphate phosphatase (EPPase) gene expression levels in chilled eggs (whose diapause had been terminated by chilling to 5 °C for 90 days) exhibited no significant increase after being transferred to 25 °C, which differed from both non-diapause eggs and HCl-treated eggs. We further compared the differential temporal expressions of insulin (bombyxin-A6, -Y1, and -Z1), ecdysone signaling (EPPase and E75A), and metabolic-related (trehalose transporter 1 (Tret1) and trehalase 1 (Treh1)) as well as sorbitol dehydrogenase 2 (SDH2) genes between chilled eggs and eggs kept at 25 °C. Our results showed that all gene expressions remained at very low levels in eggs kept at 25 °C. However, in chilled eggs, differential temporal changes were detected according to different genes, with bombyxin-A6 and EPPase gene expression levels being maintained at relatively constant, high levels. Higher expression levels of the E75A, Tret1, and Treh1 genes were also detected in chilled eggs. Expressions of the SDH2 and bombyxin-Z1 genes decreased during the first 15 days and then increased between days 30 and 90 of chilling. Ecdysteroid levels and phosphorylation of glycogen synthase kinase (GSK)-3β, a downstream target of insulin signaling, were maintained at relatively higher levels in chilled eggs. These results suggested that due to relatively higher insulin and ecdysone signaling levels in chilled eggs, relatively higher glucose metabolism was sustained, leading to the continued depletion of metabolic reserves. On day 30 of chilling, as a means to adjust nutrient requirements and maintain embryonic nutrient homeostasis, SDH2 gene expression began to increase, followed by increased expression of the bombyxin-Z1 gene. Along with high expressions of the bombyxin-Z1 and SDH2 genes, a decreased sorbitol level was suggested to eventually terminate diapause in B. mori eggs. To our knowledge, this is the first study to demonstrate the correlation between insulin/ecdysone signaling and chilling-induced embryonic diapause termination. [ABSTRACT FROM AUTHOR]

Hyperinsulinemic hypoglycemias resulting from variants in the insulin receptor (INSR) gene are rare but clinically important disorders. We present a male patient in his 30s, experiencing recurrent postprandial hypoglycemic events. Endocrine evaluation revealed an elevated insulin-to-C-peptide ratio. A hypoglycemia gene panel, using next-generation sequencing, identified a heterozygous nonsense variant in the INSR gene (NM_000208.4) c.3079C > T, p.(Arg1027*). Initial treatment with diazoxide reduced hypoglycemic symptoms and led to weight loss and decreased hemoglobin A1c due to reduced compensatory carbohydrate intake. However, limiting side effects on diazoxide prompted a treatment switch to lanreotide with maintained absence of hypoglycemic events. This case highlights the importance of considering variants in the INSR gene as a differential diagnosis in hyperinsulinemic hypoglycemia cases, even in adults. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus (DM) has a millennia-long history, with early references dating back to ancient Egypt and India. However, it was not until the 20th century that the connection between diabetes and insulin was fully understood. The sequencing of insulin in the 1950s initiated the convergence of biotechnology and diabetes management, leading to the development of recombinant human insulin in 1982. This marked the start of peptide-based therapies in DM. Recombinant peptides for DM treatment: Numerous recombinant peptides have been developed since, starting with modified insulin molecules, with the aim of bettering DM management through fine-tuning the glycemic response to insulin. Peptide-based therapies in DM have expanded substantially beyond insulin to include agonists of Glucagon-like peptide-1 receptor and Glucose-dependent insulinotropic polypeptide receptor, glucagon receptor antagonists, and even peptides exerting multiple receptor agonist effects, for better metabolic control. Insulin pumps, continuous glucose monitoring, and automated insulin delivery systems: The development of modern delivery systems combined with real-time glucose monitoring has significantly advanced diabetes care. Insulin pumps evolved from early large devices to modern sensor-augmented pumps with automated shutoff features and hybrid closed-loop systems, requiring minimal user input. The second-generation systems have demonstrated superior outcomes, proving highly effective in diabetes management. Islet cell transplantation, organoids, and biological pancreas augmentation represent innovative approaches to diabetes management. Islet cell transplantation aims to restore insulin production by transplanting donor beta cells, though challenges persist regarding graft survival and the need for immunosuppression. Organoids are a promising platform for generating insulin-producing cells, although far from clinical use. Biological pancreas augmentation relies on therapies that promote beta-cell (re)generation, reduce stress, and induce immune tolerance. Further biotechnology-driven perspectives in DM will include metabolic control via biotechnology-enabled tools such as custom-designed insulin hybrid molecules, machine-learning algorithms to control peptide release, and engineering cells for optimal peptide production and secretion. [ABSTRACT FROM AUTHOR]

The article discusses the effects of tirzepatide, a dual receptor agonist, on obese diabetic ovariectomized mice. Tirzepatide was found to decrease insulin resistance, control blood glucose, and enhance β-cell function. The study also highlighted the beneficial effects of tirzepatide on markers related to β-cell survival and maintenance in isolated islets. However, the authors noted that further studies are needed to translate these findings to humans. [Extracted from the article]

Hyperglycaemia is one condition related to inflammation leading to insulin signalling impairment. This study was conducted to investigate the insulin sensitivity improvement of Sambiloto (Andrographis paniculata (Burm. f.)) Nees extract in insulin resistance-induced HepG2 (IR-HepG2) cells by stimulating insulin sensitivities and inhibiting inflammatory response. Sambiloto extract at 2 µg/mL revealed glucose uptake stimulation and up-regulating GLUT-2 and IRS-1 gene expression, and inhibited pro-inflammatory cytokine IL-6 gene expression in IR-HepG2 cells. Phytochemical analysis showed that the total phenolic level and andrografolide content of Sambiloto extract were 2.91 ± 0.04% and 1.95%, respectively. This result indicated that Sambiloto extract ameliorated insulin resistance in high glucose-induced IR-HepG2 cells via modulating the IRS-1/GLUT-2 pathway due to IL-6 inhibition. These findings suggested that Sambiloto extract had potency as an anti-inflammatory and insulin-resistance improvement in IR-HepG2 cells. [ABSTRACT FROM AUTHOR]

Objective: Caloric restriction (CR) is known to enhance insulin sensitivity and reduce the risk of metabolic disorders; however, its molecular mechanisms are not fully understood. This study aims to elucidate specific proteins and pathways responsible for these benefits. Methods: We examined adipose tissue from participants in the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study, comparing proteomic profiles from individuals after 12 and 24 months of CR with baseline and an ad libitum group. Biochemical and cell‐specific physiological approaches complemented these analyses. Results: Our data revealed that CR upregulates prostacyclin synthase (PTGIS) in adipose tissue, an enzyme crucial for producing prostacyclin (PGI2). PGI2 improves the ability of insulin to stimulate the tether‐containing UBX domain for GLUT4 (TUG) cleavage pathway, which is essential for glucose uptake regulation. Additionally, iloprost, a PGI2 analog, was shown to increase insulin receptor density on cell membranes, increasing glucose uptake in human adipocytes. CR also reduces carbonylation of GLUT4, a modification that is detrimental to GLUT4 function. Conclusions: CR enhances insulin sensitivity by promoting PTGIS expression and stimulating the TUG cleavage pathway, leading to increased GLUT4 translocation to the cell surface and decreased GLUT4 carbonylation. These findings shed light on the complex molecular mechanisms through which CR favorably impacts insulin sensitivity and metabolic health. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion While statins are effective at managing lipid levels, there is growing evidence for new‐onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP‐related genes and NODM.We performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP‐related genes, we selected 11 candidate genes (IGF1, IGF2, IGF1R, INSR, IRS1, IRS2, PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.A total of 602 patients were analysed, including 71 (11.8%) with statin‐induced NODM. After adjustment, IGF1R rs2715439, INSR rs1799817, INSR rs2059807 and PIK3R1 rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin‐induced NODM lost their significance in patients with DM prior to statin therapy.This study revealed the ISP‐related genetic effects, specifically involving genes such as INSR, IGF1R and PIK3R1, in the development of statin‐induced NODM. Our findings suggest a potential mechanism of statin‐induced NODM related to ISP‐related genetic variants. [ABSTRACT FROM AUTHOR]

Background and aim: Head and neck paragangliomas (HNPGN) are tumours that carry significant morbidity The role of the stroma in the pathogenesis of HNPGN is not completely understood. This study explores the profile of fibroblasts and macrophages in HNPGN. Methods: Ten patients undergoing HNPGN surgery were recruited. CD68 and CD163 immunohistochemistry was performed for macrophage analysis; CD90 and podoplanin (PDPN) expression was examined to identify fibroblasts. RT-qPCR was performed on HNPGN tissue for macrophage- and fibroblast-associated molecules. Fibroblast cultures were established from HNPGN were analysed by RT-qPCR and flowcytometry. Confocal microscopy for MCT1 and MCT4 was performed in HNPGN. Results: CD68 and CD163 expressing macrophages were noted in HNPGN. CD90 and PDPN expressing cells were present in HNPGN. RT-qPCR analysis showed expression of phenotypic and functional macrophage- and fibroblast-associated molecules in HNPGN. RT-qPCR analysis of fibroblasts cultured from HNPGN confirmed the expression of several molecules including PDPN at comparable levels to healthy tissue fibroblasts. Expression of FAP, MCT-1, insulin receptor (CD220) and insulin growth factor receptor-2 (CD222) was noted on HNPGN derived fibroblasts on flowcytometry. MCT1 and MCT4 were expressed in HNPGN tumour cells and stromal macrophages in-situ. Conclusion: Fibroblasts and macrophages are present in the HNPGN tumour microenvironment, and several macrophage and fibroblast functional markers are expressed in HNPGN. Macrophages in HNPGN tissue express metabolic markers MCT1 and MCT4. Further analysis of the fibroblast and macrophage function in HNPGN will improve our understanding of their potential roles in tumour pathogenesis. [ABSTRACT FROM AUTHOR]

Lacticaseibacillus rhamnosus SD11 (SD11) has several health benefits for the host, including antidiabetic, anti-inflammatory, and antimicrobial effects. However, the antidiabetic mechanism of SD11 has not been clearly elucidated. The current study assessed the effects of SD11 and the associated underlying mechanisms on streptozotocin (STZ)-induced diabetic mice. Compared with the normal control, SD11 supplementation for 4 weeks significantly improved the metabolic profiles, including body weight (BW), fasting blood glucose (FBG), fasting insulin level (FIN), and liver index (LI), in conjunction with a lower NAS score. A notable reduction in the liver function parameters aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and total cholesterol (TC), together with histopathology studies, supported diabetic recovery by SD11. A closer examination of two major markers for the insulin pathway, insulin receptor (INSR) and insulin substrate (IRS)-1, revealed that SD11 could exert its glucose control through the upregulation of these molecules, which were almost demolished in nontreated diabetic livers. Additionally, SD11-treated mice exhibited alleviation of oxidative stress enzymes; downregulation of proinflammatory cytokines, including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; and decreased infiltration of macrophages into liver tissue. These findings were concomitant with the preservation of the tight junction proteins occludin and zona occludin (ZO)-1, which in turn lowered the levels of the inflammatory cytokines IL-1β and TNF-α and prevented colon tissue injury to some extent. Notably, the results for the SD11 control mice were identical to those for the normal control mice. Overall, our findings that SD11 delays liver deterioration and reduces colon lesions in diabetic mice provide evidence for the use of SD11 as an effective strategy to improve diabetes-related symptoms. [ABSTRACT FROM AUTHOR]

Aims Increased prevalence of acute myocardial infarction related to diabetes and insulin resistance is associated with an elevated risk of unstable atherosclerotic plaques, which are characterized by reduced vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) and increased inflammation. Thus, insulin resistance may reduce plaque stability, as deleting insulin receptors (IRs) in VSMCs decreases their proliferation and enhances apoptosis. Methods and results Direct effects of insulin on VSMCs to alter plaque composition were studied using mice with double knockout of ApoE and IR genes in VSMCs with SMIRKO/ApoE−/−, Myh11-CreERT2EYFP+/ApoE−/−, and Myh11-CreERT2EYFP+IRKO/ApoE−/− mice, which were also used for lineage tracing studies. Compared with ApoE−/− mice, SMIRKO/ApoE−/− mice exhibited more atherosclerotic plaques, which contained less VSMCs and collagen but increased levels of VSMC apoptosis and necrotic areas. Lineage tracing studies showed that Icam1+ Vcam1+ VSMC was inflammatory, which increased in the aortas of Myh11-CreERT2EYFP+IRKO/ApoE−/− mice compared with control mice. Isolated VSMCs lacking IRs expressed higher inflammatory cytokines than cells with IRs. Cell-based studies indicated that insulin's anti-apoptotic and pro-proliferative effects in VSMCs were mediated via activation of the IR/Akt pathway, which were decreased in VSMCs from SMIRKO or high-fat diet mice. An analysis of the IR targets that regulated inflammatory cytokines in VSMCs showed that thrombospondin 1 (Thbs1) and Mmp2 were consistently increased with a loss of IRs. Insulin inhibited Thbs1 expression, but not Mmp2 expression, through p-Akt/p-FoxO1 pathways in VSMCs from ApoE−/− mice, and was impaired in cells from SMIRKO/ApoE−/− mice. Thbs1 further induced Icam1 and Mmp2 expressions in VSMCs. Conclusion Insulin via IRs has significant actions in VSMCs to decrease inflammation, apoptosis, and ECM turnover via the activation of Akt and FoxO1 pathways. The inhibition of insulin actions and related pathways related to insulin resistance and diabetes may contribute to the formation of unstable atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

Insulin resistance, stem cell dysfunction, and muscle fiber dystrophy are all age-related events in skeletal muscle (SKM). However, age-related changes in insulin isoforms and insulin receptors in myogenic progenitor satellite cells have not been studied. Since SKM is an extra-pancreatic tissue that does not express mature insulin, we investigated the levels of insulin receptors (INSRs) and a novel human insulin upstream open reading frame (INSU) at the mRNA, protein, and anatomical levels in Baltimore Longitudinal Study of Aging (BLSA) biopsied SKM samples of 27–89-year-old (yrs) participants. Using RT-qPCR and the MS-based selected reaction monitoring (SRM) assay, we found that the levels of INSR and INSU mRNAs and the proteins were positively correlated with the age of human SKM biopsies. We applied RNAscope fluorescence in situ hybridization (FISH) and immunofluorescence (IF) to SKM cryosections and found that INSR and INSU were co-localized with PAX7-labeled satellite cells, with enhanced expression in SKM sections from an 89 yrs old compared to a 27 yrs old. We hypothesized that the SKM aging process might induce compensatory upregulation of INSR and re-expression of INSU, which might be beneficial in early embryogenesis and have deleterious effects on proliferative and myogenic satellite cells with advanced age. [ABSTRACT FROM AUTHOR]

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large‐scale, population‐based prospective cohort study of 18,158 middle‐aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRβ, a transmembrane subunit of IR. In the IRβ‐defined subtypes, height showed no apparent association with the risk of IRβ‐positive CRC. In contrast, a multivariable HR of IRβ‐positive CRC was 1.77 (95% CI = 1.04–3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRβ‐positive CRC (multivariable HR per 5 METs‐hour/day = 0.93, 95% CI = 0.88–0.99). Meanwhile, we found no significant association between any exposure and IRβ‐negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively. What's new? The involvement of insulin receptors in colorectal carcinogenesis remains unclear. Here, the authors investigated the association of height, body mass index, and physical activity with colorectal cancer according to insulin receptor expression. In this large‐scale, population‐based study, risk of insulin receptor β‐positive colorectal cancer was elevated in individuals with obesity, whereas physical activity was associated with reduced risk. No significant association between any exposure and insulin receptor β‐negative colorectal cancer was found. The findings suggest that changes in insulin status related to obesity and physical activity may influence colorectal carcinogenesis via the insulin receptor. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori (H. pylori) is a known gastro-intestinal pathogen but implicated in extra-gastric diseases. The relationship between H. pylori infection and type 2 diabetes (T2DM) remains insufficiently elucidated, particularly in terms of molecular mediators such as microRNAs (miRNAs) and messenger RNAs (mRNAs). Objective: We aimed to characterize expression pattern of insulin signalling mRNAs and targeted miRNAs in T2DM patients exposed to H. pylori infection. Methods: We conducted a cross-sectional study among patients diagnosed with type 2 diabetes mellitus and were aged 18 to 60 years. Overnight fasting blood samples were collected and processed for plasma and serum. The plasma samples were used for glucose estimation and the serum used for H. pylori IgG screening. Total RNA was extracted from the serum with commercial kit, and mRNAs and miRNAs quantified by RT-qPCR with specific primers and under predetermined amplification conditions. Clinical data were obtained from medical records of patients. Results: Among 351 patients enrolled, 267 (76.1%) were females, 224 (63.8%) were married, and 79 (22.5%) had tertiary education. Expression level of insulin receptor mRNA was significantly lower in H. pylori positive T2DM patients compared to H. pylori negative (P <.05). There was no evidence of a difference in insulin receptor substrate 1 mRNA level (P >.05). Although not statistically significant, the expression levels of miRNA-222 and miRNA-155 in the patients exposed to H. pylori were higher than that of the unexposed group (P >.05). Conclusions: We found a significantly reduced serum insulin receptor messenger RNA level and higher levels of miRNA-222 and miRNA-155 in H. pylori exposed T2DM patients. The findings suggest a possible role of the infection in insulin signalling alteration in the patients. [ABSTRACT FROM AUTHOR]

Purpose: Amino acid transporters are expressed in the brain capillary endothelial cells that form the blood–brain barrier (BBB), and their expression levels change during the neonatal period. This study aimed to investigate the molecular mechanisms regulating amino acid transporter levels in mouse brain capillary endothelial cells. Methods: Capillaries were isolated from the brains of neonatal and adult mice. Activation of eukaryotic translation initiation factor 2α kinase 4 (eIF2αK4) was analyzed in MBEC4 (mouse brain capillary endothelial) cells under amino acid-depleted conditions. Protein expression was determined using western blotting and proteomic analyses. Results: Phosphorylation of eIF2α, a downstream target of eIF2αK4, was induced in the brain capillaries of neonates compared to adults. In vitro experiments using MBEC4 cells revealed that amino acid depletion induced eIF2α phosphorylation and expression of the amino acid transporter, solute carrier (Slc)-7a1. The eIF2αK4 inhibitor, GCN2iB, inhibited these inductions. Proteomic analysis revealed arginine depletion-dependent induction of amino acid transporters Slc1a4, Slc3a2, Slc7a1, Slc7a5, and Slc38a1. These effects were also inhibited by GCN2iB, suggesting the involvement of eIF2αK4 activation. In contrast, the expression of Slc2a1, Slc16a1, Abcb1b, Abcg2, transferrin receptor, insulin receptor, claudin-1, ZO-1, and Jam1 was not suppressed by the GCN2iB treatment. Conclusions: Overall, the eIF2αK4 pathway plays a regulatory role in amino acid transporter expression in brain capillary endothelial cells and facilitates the maintenance of amino acid homeostasis in the brain. This study provides new insights into the regulatory mechanisms underlying nutrient transport across the BBB. [ABSTRACT FROM AUTHOR]

The article discusses the concept of paraptosis, a type of programmed cell death that differs from apoptosis and necrosis, and its potential in cancer therapy. Paraptosis can be triggered by natural products, leading to unique cell death mechanisms that differ from traditional pathways. Natural products like curcumin and morusin have been found to induce paraptosis in cancer cells by disrupting ion balance within cells. The article also highlights the challenges in using natural products in cancer treatment, including the lack of rigorous clinical trials and difficulties in developing them into drugs. [Extracted from the article]

Insulin Receptor Substrate 2 (IRS2) is a signaling adaptor protein for the insulin (IR) and Insulin-like Growth Factor-1 (IGF-1R) receptors. In breast cancer, IRS2 contributes to both the initiation of primary tumor growth and the establishment of secondary metastases through regulation of cancer stem cell (CSC) function and invasion. However, how IRS2 mediates its diverse functions is not well understood.Weused CRISPR/Cas9- mediated gene editing to modify endogenous IRS2 to study the expression, localization, and function of this adaptor protein. A cassette containing an auxin-inducible degradation (AID) sequence, 3x-FLAG tag, and mNeon-green was introduced at the N-terminus of the IRS2 protein to provide rapid and reversible control of IRS2 protein degradation and analysis of endogenous IRS2 expression and localization. Live fluorescence imaging of these cells revealed that IRS2 shuttles between the cytoplasm and nucleus in response to growth regulatory signals in a PI3Kdependent manner. Inhibition of nuclear export or deletion of a putative nuclear export sequence in the C-terminal tail promotes nuclear retention of IRS2, implicating nuclear export in the mechanism by which IRS2 intracellular localization is regulated. Moreover, the acute induction of IRS2 degradation reduces tumor cell invasion, demonstrating the potential for therapeutic targeting of this adaptor protein. Our data highlight the value of our model of endogenously tagged IRS2 as a tool to study IRS2 localization and function. [ABSTRACT FROM AUTHOR]

In patients with type 2 diabetes mellitus (DM), excessive gluconeogenesis is considered a major contributor to hyperglycemia. Therefore, targeting fructose 1,6‐bisphosphatase (FBPase), a key regulatory enzyme involved in gluconeogenesis, has gained interest as a potential therapeutic target for managing DM. In this study, a library of 42 structurally‐related chromone derivatives (including flavonoids, 2‐styrylchromones, and 2‐(4‐arylbuta‐1,3‐dien‐1‐yl)chromones, named as 2‐styrylchromone‐related derivatives), as well as 4‐ and 5‐styrylpyrazoles, were tested against human FBPase using a noncellular microanalysis screening system. Herbacetin, 3,4′,5,7,8‐pentahydroxyflavone, inhibited FBPase activity with an IC50 value of 6.4 ± 0.7 μM. The effects of herbacetin were also explored using an insulin‐resistant human hepatocellular carcinoma cell line (HepG2 cells). The results showed that herbacetin significantly decrease insulin resistance by promoting the phosphorylation of protein kinase B (Akt), and exhibited a capacity to ameliorate inflammation, evidenced by the modulation of the inhibitor of κB alpha (IκBα). This study provides important considerations for the design of novel FBPase inhibitors. Furthermore, it indicates a preliminary potential of herbacetin's dual action in improving insulin resistance and decreasing inflammation, suggesting the need for further investigation of this compound for addressing the complexities of type 2 DM management. [ABSTRACT FROM AUTHOR]

Oxidative stress is a pivotal factor in the pathogenesis of various cardiovascular diseases. Rhodiola, a traditional Chinese medicine, is recognized for its potent antioxidant properties. Salidroside, a phenylpropanoid glycoside derived from Rhodiola rosea, has shown remarkable antioxidant capabilities. This study aimed to elucidate the potential protective mechanisms of Rhodiola and salidroside against H2O2‐induced cardiac apoptosis in H9c2 cardiomyoblast cells. H9c2 cells were exposed to H2O2 for 4 h, and subsequently treated with Rhodiola or salidroside for 24 h. Cell viability and apoptotic pathways were assessed. The involvement of insulin‐like growth factor 1 receptor (IGF1R) and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) were investigated. H2O2 (100 μM) exposure significantly induced cardiac apoptosis in H9c2 cells. However, treatment with Rhodiola (12.5, 25, and 50 μg/mL) and salidroside (0.1, 1, and 10 nM) effectively attenuated H2O2‐induced cytotoxicity and apoptosis. This protective effect was associated with IGF1R‐activated phosphorylation of ERK1/2, leading to the inhibition of Fas‐dependent proteins, HIF‐1α, Bax, and Bak expression in H9c2 cells. The images from hematoxylin and eosin staining and immunofluorescence assays also revealed the protective effects of Rhodiola and salidroside in H9c2 cells against oxidative damage. Our findings suggest that Rhodiola and salidroside possess antioxidative properties that mitigate H2O2‐induced apoptosis in H9c2 cells. The protective mechanisms involve the activation of IGF1R and subsequent phosphorylation of ERK1/2. These results propose Rhodiola and salidroside as potential therapeutic agents for cardiomyocyte cytotoxicity and apoptosis induced by oxidative stress in heart diseases. Future studies may explore their clinical applications in cardiac health. [ABSTRACT FROM AUTHOR]

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Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD. [ABSTRACT FROM AUTHOR]

Nutrient-sensing pathways undergo deregulation in aged animals, exerting a pivotal role in regulating the cell cycle and subsequent stem cell division. Nevertheless, their precise functions in governing pluripotent stem cell differentiation remain largely elusive. Here, we uncovered a significant alteration in the cellular constituents of the intestinal epithelium in aged humans and mice. Employing Drosophila midgut and mouse organoid culture models, we made an observation regarding the altered trajectory of differentiation in intestinal stem cells (ISC) during overnutrition or aging, which stems from the erroneous activation of the insulin receptor signaling pathway. Through genetic analyses, we ascertained that the nutrient-sensing pathway regulated the direction of ISC differentiation by modulating the maturation of endosomes and SOX21A transcription factor. This study elucidates a nutrient-sensing pathway-mediated mechanism underlying stem cell differentiation, offering insights into the etiology of stem cell dysfunction in aged animals, including humans. Nutrient-sensing pathways undergo deregulation in aged animals. Here the authors uncover a significant alteration in the composition of intestinal epithelial cells during aging which is caused by changes to the differentiation direction of intestinal stem cells. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) slows aging in many animals, while in some cases, the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here, we measure how Drosophila neuropeptide F (NPF) is secreted into adult circulation by EEC and find that specific EEC differentially respond to dietary sugar and yeast. Female lifespan is increased when gut NPF is genetically depleted, and this manipulation is sufficient to blunt the longevity benefit conferred by DR. Depletion of NPF receptors at insulin-producing neurons of the brain also increases female lifespan, consistent with observations where loss of gut NPF decreases neuronal insulin secretion. The longevity conferred by repressing gut NPF and brain NPF receptors is reversed by treating adults with a juvenile hormone (JH) analog. JH is produced by the adult corpora allata, and inhibition of the insulin receptor at this tissue decreases JH titer and extends lifespan in both males and females, while this longevity is restored to wild type by treating adults with a JH analog. Overall, EEC of the gut modulate Drosophila aging through interorgan communication mediated by a gut–brain–corpora allata axis, and insulin produced in the brain impacts lifespan through its control of JH titer. These data suggest that we consider how human incretins and their analogs, which are used to treat obesity and diabetes, may impact aging. [ABSTRACT FROM AUTHOR]

Recent studies have shown that pharmacologic weight loss with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and combination therapies is approaching magnitudes achieved with surgery. However, as more weight loss is achieved, there is concern for potential adverse effects on muscle quantity, composition, and function. This primer aims to address whether muscle-related changes associated with weight loss treatments such as GLP-1 RAs may be maladaptive (ie, adversely affecting muscle health or function), adaptive (ie, a physiologic response to weight loss maintaining or minimally affecting muscle health or function), or perhaps an enhanced response to weight loss (ie, improved muscle health or function after treatment). Based on contemporary evidence with the addition of studies using magnetic resonance imaging, skeletal muscle changes with GLP-1 RA treatments appear to be adaptive: changes in muscle volume z-score indicate a change in muscle volume that is commensurate with what is expected given aging, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and prefrailty may influence the selection of appropriate candidates for these therapies because of risk for sarcopenia. Several pharmacologic treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. For future development of GLP-1-based therapies (and other therapies) designed for weight loss, as well as for patient-centered treatment optimization, the introduction of more objective and comprehensive ways of assessing muscle health (including accurate and meaningful assessments of muscle quantity, composition, function, mobility, and strength) is important for the substantial numbers of patients who will likely be taking these medications well into the future. [ABSTRACT FROM AUTHOR]

Objective. The objective of this study was to identify a unique serum profile of circulating miRNAs and inflammatory markers in patients with degenerative cervical myelopathy (DCM) compared with healthy controls (HC). Summary of Background Data. Currently, DCM is diagnosed with a combination of history, physical examination, and close correlation to advanced imaging. To date, no serum marker has been identified to be diagnostic of this condition. Methods. Whole venous blood was collected from patients with DCM as well as healthy age-matched and gender-matched controls. miRNA was extracted from venous blood, and a screening analysis was initially conducted to identify miRNA dysregulation in DCM patients. RT-qPCR was used to analyze the expression of 2 specific miRNAs based on screening analysis and literature review. Bioinformatics analysis was used to identify gene networks and potential targets of the miRNA. In addition, the serum inflammatory profile of DCM and HC groups was differentiated using a pro-inflammatory panel. Results. Thirty-six patients were enrolled in the DCM group (36.1% male, 61.5 ±9.5 y), while 35 patients were enrolled in the HC group (31.4% male, 57.5± 8.9 y). Of the 15 total miRNAs differentially expressed between DCM and HC groups, two were selected for further analysis: miR-223-3p (upregulated) and miR-451a (downregulated). Functional gene network analysis revealed the highest-ranking gene network was involved in neurological disease, while the most overexpressed miRNA in this network (miR-233-3p) was noted to have over 100 targets, including CDKN1B and the insulin receptor. Serum cytokine analysis showed significant upregulation of several pro-in- flammatory cytokines in the DCM cohort compared with the HC group. Conclusion. DCM patients demonstrated a set of unique circulating miRNAs in addition to a different serum inflammatory profile compared with HC. These miRNAs may potentially serve as targets for future therapeutic intervention or diagnostic/ prognostic testing. [ABSTRACT FROM AUTHOR]

Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence. Synopsis: Heterochromatin plays an essential role in the regulation of genome stability, gene expression, and cellular functions, but the factors responsible for its formation and maintenance remain incompletely characterized. This study shows that insulin receptor tyrosine kinase substrate (IRTKS) can undergo liquid‒liquid phase separation and counteract cellular senescence by regulating heterochromatin organization. IRTKS is required for heterochromatin architecture. IRTKS undergoes liquid-liquid phase separation and infiltrates into heterochromatin condensates. IRTKS facilitates HP1α SUMOylation by Ubc9 and its subsequent stabilization. IRTKS deficiency accelerates cellular senescence. IRTKS contributes to the formation and maintenance of HP1α-driven heterochromatin condensates by promoting HP1α SUMOylation. [ABSTRACT FROM AUTHOR]